Tracking Ca²⁺ Dynamics in NOD Mouse Islets During Spontaneous Diabetes Development

The mechanisms accounting for the functional changes of α- and β-cells over the course of type 1 diabetes (T1D) development are largely unknown. Permitted by our established technology of high spatiotemporal resolution imaging of cytosolic Ca²⁺ ([Ca²⁺]_c) dynamics on fresh pancreas tissue slices, we tracked the [Ca²⁺]_c dynamic changes, as the assessment of function, in islet α- and β-cells of female nonobese diabetic (NOD) mice during the development of spontaneous diabetes. We showed that, during the phases of islet inflammation, 8 mmol/L glucose-induced synchronized short [Ca²⁺]_c events in β-cells were diminished, whereas long [Ca²⁺]_c events were gradually more triggerable at substimulatory 4 and 6 mmol/L glucose. In the islet destruction phase, the synchronized short [Ca²⁺]_c events in a subset of β-cells resumed at high glucose condition, while the long [Ca²⁺]_c events were significantly elevated already at substimulatory glucose concentrations. In the α-cells, the glucose sensitivity of the [Ca²⁺]_c events persisted throughout the course of T1D development. At the late islet destruction phase, the α-cell [Ca²⁺]_c events exhibited patterns of synchronicity. Our work has uncovered windows of functional recovery in β-cells and potential α-cells functional synchronization in NOD mice over the course of T1D development.

• In NOD mice β-cells, 8 mmol/L glucose–induced synchronized short [Ca²⁺]_c events diminish in the early phases of islet inflammation, and long Ca²⁺ events became more sensitive to substimulatory 4 and 6 mmol/L glucose.

• In the late islet destruction phase, the synchronized short [Ca²⁺]_c events in a subset of β-cells resumed at 8 mmol/L glucose, while the long Ca²⁺ events were significantly elevated at substimulatory glucose concentrations.

• In the α-cells, the glucose sensitivity of the [Ca²⁺]_c events persisted throughout the course of type 1 diabetes development.

• α-Cell [Ca²⁺]_c events occasionally synchronize in the islets with severe β-cell destruction.